The Yellow Fever Virus Vaccine Induces a Broad and Polyfunctional Human Memory CD8+ T Cell Response1

• Authors: Rama Akondy, Emory University; Nathan D. Monson, Emory University; Joseph Darrell Miller, Emory University; Srilatha Edupuganti, Emory University; Dirk Teuwen, Sanofi Pasteur; Hong Wu, Emory University; Farah Quyyumi, Emory University; Seema Garg, Emory University; John D Altman, Emory University; Carlos Del Rio, Emory University; Harry L Keyserling, Emory University; Alexander Ploss, Rockefeller University; Charles M. Rice, Rockefeller University; Walter Orenstein, Emory University; Mark Mulligan, Emory University; Rafi Ahmed, Emory University
• Journal Title: Journal of Immunology
• Volume: Volume 183, Number 12
• Publisher: American Association of Immunologists | 2009-12-15, Pages 7919-7930
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.4049/jimmunol.0803903
• Subjects: Health Sciences, Immunology

Abstract

The live yellow fever vaccine (YF-17D) offers a unique opportunity to study memory CD8+ T cell differentiation in humans following an acute viral infection. We have performed a comprehensive analysis of the virus-specific CD8+ T cell response using overlapping peptides spanning the entire viral genome. Our results showed that the YF-17D vaccine induces a broad CD8+ T cell response targeting several epitopes within each viral protein. We identified a dominant HLA-A2-restricted epitope in the NS4B protein and used tetramers specific for this epitope to track the CD8+ T cell response over a 2 year period. This longitudinal analysis showed the following. 1) Memory CD8+ T cells appear to pass through an effector phase and then gradually down-regulate expression of activation markers and effector molecules. 2) This effector phase was characterized by down-regulation of CD127, Bcl-2, CCR7, and CD45RA and was followed by a substantial contraction resulting in a pool of memory T cells that re-expressed CD127, Bcl-2, and CD45RA. 3) These memory cells were polyfunctional in terms of degranulation and production of the cytokines IFN-γ, TNF-α, IL-2, and MIP-1β. 4) The YF-17D-specific memory CD8+ T cells had a phenotype (CCR7−CD45RA+) that is typically associated with terminally differentiated cells with limited proliferative capacity (TEMRA). However, these cells exhibited robust proliferative potential showing that expression of CD45RA may not always associate with terminal differentiation and, in fact, may be an indicator of highly functional memory CD8+ T cells generated after acute viral infections.